EFFECTS OF TETRABENAZINE ON METHAMPHETAMINE-INDUCED HYPERACTIVITY IN MICE ARE DEPENDENT ON ORDER AND TIME-COURSE OF ADMINISTRATION

The ambulation-increasing effect of methamphetamine (MAP: 2 mg/kg SC) in mice persisted for about 3 h. Tetrabenazine (TBZ: 4 mg/kg SC), a de pleter of monoamines from the cytoplasmic pool did not increase ambula tion on its own. Pretreatment with TBZ at 1.5 h before administration of MAP inhibited the stimulant effect of MAP. In contrast, combined ad ministration of two drugs resulted in a transient but considerable enh ancement of MAPs stimulant effect. Post-MAP treatment with TBZ at 0.5- 2 h hardly modified MAPs behavioral effects. In contrast, 3-6 h post-M AP treatment with TBZ induced a transient increase in activity, althou gh the stimulant effect of MAP had already disappeared. The maximum in crease in ambulatory stimulation was produced by 4-h post-MAP treatmen t with TBZ. The inhibitory effect of TBZ pretreatment on MAP-induced h yperactivity, as well as the transient hyperactivity elicited by TBZ w hen administered along with MAP, or 4 h after MAP, was dose-dependent. Preliminary studies revealed that transient hyperactivity was never p roduced by combination of GBR-12909 (a selective dopamine reuptake inh ibitor) with TBZ or MAP with oxypertine (a selective norepinephrine re leaser/depleter), but produced by combination of nialamide (a monoamin e oxidase inhibitor) with TBZ. Inhibition of MAPs effects by TBZ pretr eatment suggests that enhancement of dopamine release from cytoplasmic pool, and inhibition of dopamine reuptake by MAP, are involved in MAP s acute behavioral effects. Further, the fact that neither TBZ adminis tration following GBR12909 pretreatment, nor oxypertine treatment foll owing MAP pretreatment, elicited transient hyperactivity suggests that dopamine is involved in hyperactivity elicited by post-MAP treatment with TBZ. It is also suggested that inhibition of monoamine oxidase (M AO) by MAP and dopamine displacement by TBZ may be responsible for the transient stimulation produced by 36 h post-MAP treatment with TBZ. I t is hypothesized that the MAO inhibitory action of MAP persists after cessation of its acute stimulant effect, possibly up to 6 h after adm inistration. Copyright (C) 1997 Elsevier Science Inc.